Manufacturing of Drug Product, Dual Aβ/tau Vaccine for Clinical Trials

项目摘要 免疫疗法仍然被认为是预防AD的一种有前途的治疗策略。数据来自 各种免疫治疗研究支持我们的长期信条，即免疫原性AD 当疫苗同时针对Aβ和Tau病理时，至少可以延缓疾病的进展 分子在疾病的早期阶段，甚至在有阿尔茨海默病风险的健康人中。最近美国食品和药物管理局 宣布紧急加速批准单抗Aducanumab用于治疗早期AD。 然而，使用非常昂贵的单抗作为健康疾病的预防性治疗是不切实际的。 受试者需要经常(每月)服用高浓度药物(700-800毫克 每次静脉注射)这种免疫疗法。相比之下，几乎所有有效的疫苗都是有效的 当它们被用作预防性治疗时。因此，IMM-NIA的主要目标是 合作的U01 AG-60965计划是生产针对tau或Aβ的单一疫苗，以及 双重疫苗，同时针对两种病理分子。基于这一范围内的目标 在目前的项目中，我们与盖茨生物制造设施(GBF)合作制造了 双联疫苗的两种成分，AV-1980R和AV-1959R重组蛋白(药物 物质)，以GMP格式用于第一人第一阶段临床试验。GBF开发了两种药物 在临床前启用IND中测试的物质，AV-1980R和AV-1959R 安全/毒理学研究。在GMP生产双重疫苗的第一组分的同时， AV-1980R，启动并将于2022年8月完成，出乎意料的是，技术困难 第二个部件--AV-1959R的生产产生了。AV-1959R似乎是一种更 比AV-1980R更容易聚集的蛋白质，这导致了不同的配方和大量的 AV-1959R产品成品率下降。虽然这些困难对单身人士来说并不重要 疫苗，AV-1959R或AV-1980R(IND准备工作正在进行中)，制造/配方 在准备和提交IND之前，需要对双重疫苗进行优化。GBF团队 已经确定了一条提高蛋白质产量的技术路线，并根据他们的 体验和分析工具，如动态光散射、十二烷基硫酸钠-PAGE和反相 高效液相色谱柱。因此，本项目旨在开发一种AV-1959R的配方，它将增加 AV-1959R的生产良率，支持短期和长期稳定，并制造出最终的 CGMP级双联疫苗(药品)。申请的资金将用于支付加工费用。 AV-1959R的开发/处方优化、cGMP AV-1959R药物生产 物质、双重疫苗配方、灌装/冷冻干燥、包装和释放试验、稳定性 药品双联疫苗。

Project Summary Immunotherapy is still considered a promising therapeutic strategy for AD prevention. Data from various immunotherapeutic studies support our long-standing tenet that immunogenic AD vaccines could at least delay disease progression when they target both Aβ and Tau pathological molecules at an early stage of the disease or even in healthy people at AD risk. Recently FDA announced emergency accelerated approval of mAb Aducanumab for treatment of early AD. However, it is impractical to use very expensive mAbs as a preventive treatment for healthy subjects due to the need for frequent (monthly) administration of high concentrations (700-800mg per IV injection) of this immunotherapeutic. In contrast, almost all effective vaccines are effective when they are used as a preventive treatment. Accordingly, the major goal of the IMM-NIA cooperative U01 AG-60965 program is to manufacture single vaccines targeting tau or Aβ, and a dual vaccine, targeting both pathological molecules together. Based on this goal within the scope of the current program, we worked with Gates Biomanufacturing Facility (GBF) to manufacture two components of the dual vaccine, AV-1980R and AV-1959R recombinant proteins (drug substances), in a GMP format for first-human Phase I clinical trials. GBF developed two drug substances, AV-1980R and AV-1959R, that were tested in pre-clinical IND-enabling safety/toxicology studies. While GMP manufacturing of the first component of the dual vaccine, AV-1980R, is initiated and will be completed in August 2022, unexpectedly, technical difficulties arose with the production of the second component, AV-1959R. AV-1959R appeared to be a more aggregation-prone protein than AV-1980R, which led to a different formulation and a substantial decrease in AV-1959R production yield. While these difficulties are not significant for single vaccines, AV-1959R or AV-1980R (IND preparation is ongoing), manufacturing/formulation optimization is required for the dual vaccine prior to preparation and submission of IND. GBF team has identified a technical path forward to protein yield increase and formulation based on their experience and analytical tools such as dynamic light scattering, SDS-PAGE, and reverse-phase HPLC. Therefore, this project aims to develop a formulation for AV-1959R, which will increase the production yield of AV-1959R, support short and long-term stability, and manufacture a final cGMP grade dual vaccine (drug product). The requested funds will cover the cost of process development/formulation optimization of AV-1959R, manufacturing of cGMP AV-1959R drug substance, formulation of dual vaccine, filling/lyophilization, packaging, and release tests, stability of drug product dual vaccine.